DESCRIPTION (Applicant's abstract): The ability of the arterial chemoreceptors (CRs) to modulate ventilation is not fixed, but can be altered following acute or chronic changes in CR activity. However, the contribution of alterations in the central nervous system integration of CR afferent inputs to the responses observed during hypoxia is presently unknown. Recent work in our lab has demonstrated that high frequency carotid sinus nerve stimulation can potentiate or depress subsequent synaptic inputs to neurons in the nucleus of the solitary tract (NTS), the initial site of central integration of arterial chemoreceptor inputs. The present proposal seeks to extend these observations and examine the physiological and pharmacological mechanisms mediating the integration of CR inputs following exposure to hypoxia in adult animals. This proposal will test the general hypothesis that hypoxia is associated with enhanced arterial chemoreflex function which is mediated, at least in part, by changes in CR afferent integration within the NTS. The specific hypotheses to be tested are: 1. The enhanced CR reflex following brief, 5-15 minutes, hypoxia is the result of PKC mediated potentiation of NMDA excitation and/or PKC attenuation of GABA inhibition; 2. The enhanced CR reflex following chronic hypoxia (1 week) is the result of up-regulation of excitatory neurotransmitter receptors and/or down-regulation of inhibitory neurotransmitter receptors. Microinjection, electrophysiological and molecular techniques will be used to characterize how prolonged activation of the arterial chemoreceptors alters the responses and phenotype of NTS neurons. The in vivo studies will provide a comprehensive analysis of the plasticity of chemoreceptor afferent integration in the intact, adult animal, while the molecular studies will provide mechanistic insights into the changes observed in the whole animal. The proposed studies will provide a detailed, mechanistic overview of the plasticity of CR afferent integration within the NTS following acute and chronic changes in arterial blood gasses. This information will prove useful in understanding chemoreflex function in situations where blood gas levels change for brief periods (sleep, diving, exercise, hemorrhage) and prolonged periods (sojourns to high altitude, congestive heart failure).